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Diagnostic Microdosing Approach to Study Gemcitabine Resistance

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journal contribution
posted on 22.09.2016, 00:00 by Tiffany M. Scharadin, Hongyong Zhang, Maike Zimmermann, Sisi Wang, Michael A. Malfatti, George D. Cimino, Kenneth Turteltaub, Ralph de Vere White, Chong-xian Pan, Paul T. Henderson
Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. We determined whether subtherapeutic “microdoses” of gemcitabine are incorporated into DNA at levels that correlate to drug cytotoxicity. A pair of nearly isogenic bladder cancer cell lines differing in resistance to several chemotherapy drugs were treated with various concentrations of 14C-labeled gemcitabine for 4–24 h. Drug incorporation into DNA was determined by accelerator mass spectrometry. A mechanistic analysis determined that RRM2, a DNA synthesis protein and a known resistance factor, substantially mediated gemcitabine toxicity. These results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.